PROJECT SUMMARY Individuals with type 2 diabetes (T2D) have up to a 2.8-fold greater fracture risk than non-diabetics and worse clinical outcomes after a fracture, including higher morbidity and increased mortality rates compared to non- diabetics. Thus, due to the huge and growing number of affected individuals and profound personal and health care costs, diabetic skeletal fragility is an important public health concern. Patients with T2D have normal to high bone mineral density, which usually is protective against fractures. Thus, the mechanisms underlying diabetic skeletal fragility are poorly understood, making it difficult for clinicians to identify those at risk and develop appropriate interventions to prevent fractures. Because BMD is normal or high in T2D, deficits in bone quality or microarchitecture have been implicated in diabetic skeletal fragility. Advanced glycation endproducts (AGEs) result from non-enzymatic biochemical reactions between reduced extracellular sugars and amino acid residues on proteins, including collagen, and accumulation of AGEs in various tissues are involved in the pathogenesis of many diabetic complications. Accumulation of AGEs in bone can deteriorate bone's mechanical integrity. Our overall goals are to determine the biomechanical mechanisms underlying increased skeletal fragility in patients with T2D, and to identify clinical tools that may assist in predicting fracture risk and preventing fractures in T2D. In a cross-sectional study of adults with T2D and age- and sex-matched non- diabetic controls undergoing total hip replacement surgery, we will collect femoral head and neck specimens, assess microarchitecture by microcomputed tomography, measure mechanical properties by reference point indentation and compression testing, quantify microdamage in 3D by ultra-high resolution computed tomography (nanoCT), and measure bone AGE content by high performance liquid chromatography and fluorometric assays. Also, to determine whether clinical assessments of glycemic control and/or AGE accumulation are associated with bone AGE levels, we will utilize subjects recruited for Aim 1 to correlate serum pentosidine, skin AGE content (assessed by non-invasive skin autofluorescence) and serum HbA1c levels to the concentration of AGEs in the bone itself. This project will have high impact, as the results will provide novel information regarding the mechanisms contributing to skeletal fragility in T2D, and therefore allow for improved clinical management of diabetic patients who are susceptible to fractures.